An. Hollenberg et al., LIGAND-INDEPENDENT AND LIGAND-DEPENDENT FUNCTIONS OF THYROID-HORMONE RECEPTOR ISOFORMS DEPEND UPON THEIR DISTINCT AMINO TERMINI, The Journal of biological chemistry, 270(24), 1995, pp. 14274-14280
Isoform specificity likely plays a large role in the ability of the th
yroid hormone receptor (TR) to specifically regulate gene expression i
n both the presence and absence of its cognate ligand, triiodothyronin
e. To investigate further the mechanism of isoform specificity of huma
n TRs (TR alpha 1 and TR beta 1), we have examined their functional ef
fects on positive thyroid hormone response elements (TREs) both in the
presence and absence of ligand. TR alpha 1 was greater than 2-fold mo
re potent than TR beta 1 on both TREs studied, in terms of both ligand
-independent repression and ligand-dependent stimulation. By creating
a number of chimeric and mutant receptors, we have established that th
e increased functional potency of TR alpha 1 is due to its unique amin
o terminus. Deletion or substitution of the TR alpha 1 amino terminus
leads to a loss of both its ligand-independent and -dependent function
s on positive TREs. Furthermore, the TR alpha 1 amino terminus antagon
izes homodimer formation on the positive TREs studied, TR constructs,
which contain the TR alpha 1 amino terminus, are unable to form homodi
mers and form exclusively heterodimers with RXR alpha on direct repeat
and palindromic TREs. Deletion of the amino terminus from either TR i
soform leads to preferential homodimer formation, which suggests that
the TR amino terminus is important for relative heterodimerization cap
ability. From these data, we conclude that TR alpha 1 isoform specific
ity on positive TREs resides predominantly in its amino terminus throu
gh its ability to favor heterodimerization with the retinoid X recepto
r or other nuclear proteins.